The newly identified variations, found in a gene never before linked to Alzheimer's, occur rarely in the population, making them hard for researchers to identify. But they're important because individuals who carry these variants are at substantially increased risk of the disease.
Finding mutations linked to Alzheimer's disease means it may be possible to identify more people at risk years before they develop any symptoms. These patients could be monitored carefully for early signs of Alzheimer's and possibly even get treatments to slow the progression of the disease.
As in many genetic studies of Alzheimer's, Carlos Cruchaga from Washington University School of Medicine in St. Louis and his co-investigators analyzed DNA from people in families in which multiple members were affected by the disease.
They sequenced all the protein-coding genes from several individuals in each of the 14 families, using a technique called whole exome sequencing. Some of these family members had an Alzheimer's diagnosis but others did not.
The investigators compared DNA from affected individuals in a family to those in the same family who didn't have the disorder. Eventually, they identified two families that carried the same variation in the phospholipase-D 3 gene (PLD3). The variation was present in affected family members but not in the elderly family members who did not have Alzheimer's disease.
Additional experiments conducted in the laboratory showed that when the PLD3 gene is active, levels of amyloid-beta decline. This substance aggregates in the brains of Alzheimer's patients to form plaques. When the researchers decreased expression of PLD3, levels of amyloid-beta increased.
The researchers said that the experiment strongly suggested that PLD3 is influencing Alzheimer's disease risk by regulating the activity of the gene that makes amyloid.
The study is published in the journal Nature.